The liver has an enormous capacity to regenerate, as demonstrated by the 2/3 partial hepatectomy model in rodents. In addition, the liver has a stem cell compartment acting as a backup regenerative system. Activation of the stem cell compartment occurs when hepatocytes are functionally compromised, are unable to divide, or both. In stem cell-aided liver regeneration, progeny of the stem cells multiply in an amplification compartment composed of hepatic oval cells. Recent studies have suggested that bone marrow cells can differentiate down the hepatic lineage. We have shown that bone marrow (BM) cells are able to produce hepatic oval cells, while others have only shown that BM cells can contribute to the end product of hepatocytes and bile duct epithelial cells in the rodent. The origins of oval cells thus remain controversial and several key questions remain. The foremost questions are: what is the origin of hepatic oval cells; and what determines the magnitude of their proliferative response to certain hepatic injuries? The studies proposed in this application are designed to determine the contribution of the BM to oval cell-mediated repair of liver injury. These experiments will also evaluate the role of BM-derived stem cell differentiation as opposed to cell fusion in oval cell-mediated liver repair. Finally, involvement of the chemokine stromal cell derived factor- 1 (SDF-1) in BM-derived stem cell migration to the liver, and in oval cell homing within the liver, will be determined. These studies will determine the extent each of these mechanisms play in the oval cell-aided hepatic regenerative process. We will pursue the following specific aims: Specific Aim I. To determine the degree to which BM-derived stem cells contribute to oval cell-mediated liver regeneration and to assess the level of donor repopulation resulting from fusion versus differentiation. Specific Aim II. To determine whether transplanted hepatic oval cells maintain sufficent plasticity to differentiate into mature cells unrelated to liver. Specific Aim III. To determine the functional role of SDF-1 in oval cell activation and as well as targeting BM derived oval cells to specific areas of injury within the liver. It is anticipated that the proposed studies will yield new and significant data about the mechanisms of governing the bone marrow contribution to liver regeneration and signals involved in oval cell activation, proliferation and differentiation.